16-2109556-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001009944.3(PKD1):​c.5611G>A​(p.Ala1871Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00648 in 1,611,596 control chromosomes in the GnomAD database, including 55 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0043 ( 1 hom., cov: 33)
Exomes 𝑓: 0.0067 ( 54 hom. )

Consequence

PKD1
NM_001009944.3 missense

Scores

5
14

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 1.33
Variant links:
Genes affected
PKD1 (HGNC:9008): (polycystin 1, transient receptor potential channel interacting) This gene encodes a member of the polycystin protein family. The encoded glycoprotein contains a large N-terminal extracellular region, multiple transmembrane domains and a cytoplasmic C-tail. It is an integral membrane protein that functions as a regulator of calcium permeable cation channels and intracellular calcium homoeostasis. It is also involved in cell-cell/matrix interactions and may modulate G-protein-coupled signal-transduction pathways. It plays a role in renal tubular development, and mutations in this gene cause autosomal dominant polycystic kidney disease type 1 (ADPKD1). ADPKD1 is characterized by the growth of fluid-filled cysts that replace normal renal tissue and result in end-stage renal failure. Splice variants encoding different isoforms have been noted for this gene. Also, six pseudogenes, closely linked in a known duplicated region on chromosome 16p, have been described. [provided by RefSeq, Oct 2008]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.0155184865).
BP6
Variant 16-2109556-C-T is Benign according to our data. Variant chr16-2109556-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 256979.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2109556-C-T is described in Lovd as [Benign]. Variant chr16-2109556-C-T is described in Lovd as [Likely_benign].
BS1
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00434 (661/152352) while in subpopulation NFE AF= 0.00731 (497/68024). AF 95% confidence interval is 0.00678. There are 1 homozygotes in gnomad4. There are 291 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
BS2
High AC in GnomAd4 at 661 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
PKD1NM_001009944.3 linkc.5611G>A p.Ala1871Thr missense_variant 15/46 ENST00000262304.9 NP_001009944.3

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
PKD1ENST00000262304.9 linkc.5611G>A p.Ala1871Thr missense_variant 15/461 NM_001009944.3 ENSP00000262304.4 P98161-1

Frequencies

GnomAD3 genomes
AF:
0.00434
AC:
661
AN:
152234
Hom.:
1
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00150
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00353
Gnomad ASJ
AF:
0.000576
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00517
Gnomad FIN
AF:
0.000659
Gnomad MID
AF:
0.00949
Gnomad NFE
AF:
0.00731
Gnomad OTH
AF:
0.00525
GnomAD3 exomes
AF:
0.00425
AC:
1044
AN:
245780
Hom.:
4
AF XY:
0.00449
AC XY:
602
AN XY:
133936
show subpopulations
Gnomad AFR exome
AF:
0.00102
Gnomad AMR exome
AF:
0.00230
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00549
Gnomad FIN exome
AF:
0.00129
Gnomad NFE exome
AF:
0.00659
Gnomad OTH exome
AF:
0.00466
GnomAD4 exome
AF:
0.00671
AC:
9789
AN:
1459244
Hom.:
54
Cov.:
34
AF XY:
0.00663
AC XY:
4810
AN XY:
725874
show subpopulations
Gnomad4 AFR exome
AF:
0.000926
Gnomad4 AMR exome
AF:
0.00249
Gnomad4 ASJ exome
AF:
0.0000766
Gnomad4 EAS exome
AF:
0.0000504
Gnomad4 SAS exome
AF:
0.00598
Gnomad4 FIN exome
AF:
0.00161
Gnomad4 NFE exome
AF:
0.00782
Gnomad4 OTH exome
AF:
0.00561
GnomAD4 genome
AF:
0.00434
AC:
661
AN:
152352
Hom.:
1
Cov.:
33
AF XY:
0.00391
AC XY:
291
AN XY:
74508
show subpopulations
Gnomad4 AFR
AF:
0.00149
Gnomad4 AMR
AF:
0.00353
Gnomad4 ASJ
AF:
0.000576
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00538
Gnomad4 FIN
AF:
0.000659
Gnomad4 NFE
AF:
0.00731
Gnomad4 OTH
AF:
0.00520
Alfa
AF:
0.00438
Hom.:
2
Bravo
AF:
0.00479
TwinsUK
AF:
0.00701
AC:
26
ALSPAC
AF:
0.00623
AC:
24
ESP6500AA
AF:
0.00137
AC:
6
ESP6500EA
AF:
0.00572
AC:
49
ExAC
AF:
0.00411
AC:
495
EpiCase
AF:
0.00780
EpiControl
AF:
0.00719

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:10
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Benign:5
Likely benign, criteria provided, single submitterclinical testingGeneDxFeb 08, 2021This variant is associated with the following publications: (PMID: 17582161, 22608885, 30647506) -
Likely benign, no assertion criteria providedclinical testingLaboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)-- -
Likely benign, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenNov 01, 2024PKD1: BP4, BS2 -
Benign, criteria provided, single submitterclinical testingAthena DiagnosticsFeb 25, 2019- -
Likely benign, criteria provided, single submitternot providedBreakthrough Genomics, Breakthrough Genomics-- -
Polycystic kidney disease, adult type Benign:2
Likely benign, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsApr 01, 2022- -
Benign, criteria provided, single submitterclinical testingARUP Laboratories, Molecular Genetics and Genomics, ARUP LaboratoriesSep 25, 2019- -
not specified Benign:1
Benign, no assertion criteria providedclinical testingGenome Diagnostics Laboratory, University Medical Center Utrecht-- -
Polycystic kidney disease Benign:1
Likely benign, no assertion criteria providedclinical testingDepartment of Pathology and Laboratory Medicine, Sinai Health System-The PKD1 p.Ala1871Thr variant was identified in 2 of 460 proband chromosomes (frequency: 0.004) from individuals or families with ADPKD, being classified as a polymorphism/likely neutral (Rossetti 2007, Rossetti 2012, Tan 2009, Tan 2014). The variant was identified in dbSNP (ID: rs144137200) as “With Likely benign allele”, Clinvitae and ClinVar (classification likely benign, submitter Prevention Genetics), and the ADPKD Mutation Database (classification likely neutral); but was not identified in GeneInsight-COGR, MutDB, PKD1-LOVD, and PKD1-LOVD 3.0. This variant was also identified in the 1000 Genomes Project in 8 of 5000 chromosomes (frequency: 0.002), HAPMAP-EUR in 3 of 1006 chromosomes (frequency: 0.003)/-AMR in 3 of 694 chromosomes (frequency: 0.0043)/-SAS in 2 of 978 chromosomes (frequency: 0.002), the NHLBI GO Exome Sequencing Project in 49 of 8560 European American alleles (freq. 0.006) and in 6 of 4374 African American alleles (freq. 0.001), the genome Aggregation Database (beta, October 19th 2016) in 1142 (4 homozygous) of 272522 chromosomes (freq. 0.004) and in the Exome Aggregation Consortium database (August 8th 2016) 485 (4 homozygous) of 104730 chromosomes (freq. 0.0046) in the following populations: European (Non-Finnish) in 364 of 57774 chromosomes (freq. 006), South Asian in 84 of 15042 chromosomes (freq. 006), Other in 4 of 732 chromosomes (freq. 006), Latino in 20 of 10302 chromosomes (freq. 002), African in 10 of 8320 chromosomes (freq. 001), and in European (Finnish) in 3 of 4634 chromosomes (freq. 0006); but was not seen in East Asian; increasing the likelihood this could be a low frequency benign variant. In addition we cannot be certain that data from control databases is specific to PKD1 and not from one of the six PKD1 pseudogenes. The p.Ala1871 residue is not conserved in mammals and 4 out of 5 computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. -
PKD1-related disorder Benign:1
Benign, no assertion criteria providedclinical testingPreventionGenetics, part of Exact SciencesJun 22, 2019This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.091
BayesDel_addAF
Benign
-0.36
T
BayesDel_noAF
Benign
-0.28
CADD
Benign
19
DANN
Uncertain
0.99
DEOGEN2
Benign
0.19
T;.
Eigen
Benign
0.027
Eigen_PC
Benign
-0.10
FATHMM_MKL
Benign
0.64
D
LIST_S2
Uncertain
0.86
D;D
M_CAP
Uncertain
0.20
D
MetaRNN
Benign
0.016
T;T
MetaSVM
Benign
-0.83
T
MutationAssessor
Uncertain
2.6
M;M
PrimateAI
Benign
0.40
T
PROVEAN
Benign
-0.82
N;N
REVEL
Uncertain
0.30
Sift
Benign
0.28
T;T
Sift4G
Benign
0.20
T;T
Polyphen
1.0
D;D
Vest4
0.22
MVP
0.92
ClinPred
0.015
T
GERP RS
3.4
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.18
gMVP
0.39

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs144137200; hg19: chr16-2159557; COSMIC: COSV99239466; COSMIC: COSV99239466; API